Lapachone AND NAD+

Heterogeneity of the tumor microenvironment (TME) is primarily responsible for ineffective tumor treatment and uncontrolled tumor progression. Pyroptosis-based immunogenic cell death (ICD) therapy is an ideal strategy to overcome TME heterogeneity and obtain a satisfactory antitumor effect. However, the efficiency of current pyroptosis therapeutics, which mainly depends on a single endogenous or exogenous stimulus, is limited by the intrinsic pathological features of malignant cells. Thus, it is necessary to develop a synergistic strategy with a high tumor specificity and modulability...

Lung and breast cancers rank as two of the most common and lethal tumors, accounting for a substantial number of cancer-related deaths worldwide. While the past two decades have witnessed promising progress in tumor therapy, developing targeted tumor therapies continues to pose a significant challenge. NAD(P)H quinone oxidoreductase 1 (NQO1), a two-electron reductase, has been reported as a promising therapeutic target across various solid tumors. β-Lapachone (β-Lap) and deoxynyboquinone (DNQ) are two NQO1 bioactivatable drugs that have demonstrated potent antitumor effects...

AIMS: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and severe fibrosis for which effective treatment options are currently lacking. In this study, we explored the potential of beta-lapachone (βL) as a drug candidate for PSC therapy. MATERIALS AND METHODS: We employed an animal model fed a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to assess the preventive and therapeutic effects of βL...

Pancreatic cancer is among the top five leading causes of cancer-related deaths worldwide, with low survival rates. Current therapies for pancreatic cancer lack tumor specificity, resulting in harmful effects on normal tissues. Therefore, developing tumor-specific agents for the treatment of pancreatic cancer is critical. NAD(P)H:quinone oxidoreductase 1 (NQO1), highly expressed in pancreatic cancers but not in normal tissues, makes NQO1 bioactivatable drugs a potential therapy for selectively killing NQO1-positive cancer cells...

Doxorubicin (DOX) is a widely used antineoplastic drug, but its clinical use is limited by significant toxicities, such as hepatotoxicity. In this study, we evaluated the effects of β-lapachone (β-LAP), a natural quinone-containing compound, in a mouse model of DOX-induced hepatotoxicity. β-LAP was orally administered at 1.25, 2.5, and 5 mg/kg for 4 days, and a single dose of DOX (20 mg/kg) was injected intraperitoneally on the second day. Histopathological changes, liver function markers, antioxidant and inflammatory markers were assessed...

Inositol pyrophosphates (PP-InsPs) are energetic signaling molecules with important functions in mammals. As their biosynthesis depends on ATP concentration, PP-InsPs are tightly connected to cellular energy homeostasis. Consequently, an increasing number of studies involve PP-InsPs in metabolic disorders, such as type 2 diabetes, aspects of tumorigenesis, and hyperphosphatemia. Research conducted in yeast suggests that the PP-InsP pathway is activated in response to reactive oxygen species (ROS). However, the precise modulation of PP-InsPs during cellular ROS signaling is unknown...

Introduction: Lung cancer the most prevalent cause of cancer-related deaths, and current therapies lack sufficient specificity and efficacy. This study developed an injectable thermosensitive hydrogel harboring hollow copper sulfide nanoparticles and β-lapachone (Lap) (CLH) for lung tumor treatment. Methods: The hydrogel-encapsulated CLH system can remotely control the release of copper ions (Cu2+ ) and drugs using photothermal effects for non-invasive controlled-release drug delivery in tumor therapy...

Chemodynamic therapy (CDT) relies on the tumor microenvironment (e.g., high H2 O2 level) responsive Fenton-like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H2 O2 is insufficient for effective chemodynamic responses. An NAD(P)H: quinone oxidoreductase 1 (NQO1)high catalase (CAT)low therapeutic window for the use of NQO1 bioactive drug β-lapachone (β-Lap) is first identified in endometrial cancer (EC). Accompanied by NADH depletion, NQO1 catalyzes β-Lap to produce excess H2 O2 and initiate oxidative stress, which selectively suppress NQO1high EC cell proliferation, induce DNA double-strand breaks, and promote apoptosis...

Chemotherapy remains the mainstay of cancer treatment, and doxorubicin (DOX) is recommended as a first-line chemotherapy drug against cancer. However, systemic adverse drug reactions and multidrug resistance limit its clinical applications. Here, a tumor-specific reactive oxygen species (ROS) self-supply enhanced cascade responsive prodrug activation nanosystem (denoted as PPHI@B/L) was developed to optimize multidrug resistance tumor chemotherapy efficacy while minimizing the side effects. PPHI@B/L was constructed by encapsulating the ROS-generating agent β-lapachone (Lap) and the ROS-responsive doxorubicin prodrug (BDOX) in acidic pH-sensitive heterogeneous nanomicelles...

Head and neck squamous cell carcinoma (HNSCC) cells are highly heterogeneous in their metabolism and typically experience elevated reactive oxygen species (ROS) levels such as superoxide and hydrogen peroxide (H2 O2 ) in the tumor microenvironment. Tumor cells survive under these chronic oxidative conditions by upregulating antioxidant systems. To investigate the heterogeneity of cellular responses to chemotherapeutic H2 O2 generation in tumor and healthy tissue, we leveraged single-cell RNA-sequencing (scRNA-seq) data to perform redox systems-level simulations of quinone-cycling β-lapachone treatment as a source of NQO1-dependent rapid superoxide and hydrogen peroxide (H2 O2 ) production...

Nanotechnology shows the power to improve efficacy and reduce the adverse effects of anticancer agents. As a quinone-containing compound, beta-lapachone (LAP) is widely employed for targeted anticancer therapy under hypoxia. The principal mechanism of LAP-mediated cytotoxicity is believed due to the continuous generation of reactive oxygen species with the aid of NAD(P)H: quinone oxidoreductase 1 (NQO1). The cancer selectivity of LAP relies on the difference between NQO1 expression in tumors and that in healthy organs...

BACKGROUND: Nicotinamide adenine dinucleotide (NAD+ ) metabolism is involved in the entire physiopathological process and is critical to human health. Long-term imbalance in NAD+ homeostasis is associated with various diseases, including non-alcoholic fatty liver disease, diabetes mellitus, cardiovascular diseases, neurodegenerative disorders, aging, and cancer, making it a potential target for effective therapeutic strategies. Currently, several natural products that target NAD+ metabolism have been widely reported to have significant therapeutic effects, but systematic summaries are lacking...

Electron cycler-mediated extracellular reduction of the water-soluble tetrazolium salt 1 (WST1) is frequently used as tool for the determination of cell viability. We have adapted this method to monitor by determining the extracellular WST1 formazan accumulation the cellular redox metabolism of cultured primary astrocytes via the NAD(P)H-dependent reduction of the electron cycler β-lapachone by cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1). Cultured astrocytes that had been exposed to β-lapachone in concentrations of up to 3 µM remained viable and showed an almost linear extracellular accumulation of WST1 formazan for the first 60 min, while higher concentrations of β-lapachone caused oxidative stress and impaired cell metabolism...

Chemodynamic therapy (CDT) utilizes Fenton or Fenton-like reactions to convert hydrogen peroxide (H2 O2 ) into cytotoxic hydroxyl radicals (•OH) and draws extensive interest in tumor therapy. Nevertheless, high concentrations of glutathione (GSH) and insufficient endogenous H2 O2 often cause unsatisfactory therapeutic efficacy. Herein, a GSH-depleting and H2 O2 self-providing carrier-free nanomedicine that can efficiently load indocyanine green (ICG), β-lapachone (LAP), and copper ion (Cu2+ ) (ICG-Cu2+ -LAP, LICN) to mediate synergetic photothermal and chemotherapy in enhanced chemodynamic therapy is designed...

Prodrugs are one of the most common strategies for the design of targeted anticancer agents. However, their application is often hampered by the modifiable groups available on parent drugs. Herein, a carbon-carbon (C-C) bond cleavage-based prodrug activation strategy is reported, which was successfully used to design prodrugs of β-lapachone (β-lap), an ortho-quinone natural product without traditional modifiable groups for the construction of C-N/C-O bond cleavage-based prodrugs. The designed β-lap prodrug with a reactive oxygen species-specific trigger was quickly activated, releasing β-lap...

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) tumors compared to the associated normal tissues. NQO1 bioactivatable drugs, such as β-lapachone (β-lap), can be catalyzed to generate reactive oxygen species (ROS) for direct tumor killing. However, the extremely narrow therapeutic window caused by methemoglobinemia and hemolytic anemia severely restricts its further clinical translation despite considerable efforts in the past 20 years...

The compound β-lapachone, a naturally derived naphthoquinone, has been utilized as a potent medicinal nutrient to improve health. Over the last twelve years, numerous reports have demonstrated distinct associations of β-lapachone and NAD(P)H: quinone oxidoreductase 1 (NQO1) protein in the amelioration of various diseases. Comprehensive research of NQO1 bioactivity has clearly confirmed the tumoricidal effects of β-lapachone action through NAD+ -keresis, in which severe DNA damage from reactive oxygen species (ROS) production triggers a poly-ADP-ribose polymerase-I (PARP1) hyperactivation cascade, culminating in NAD+ /ATP depletion...

Cancer drug delivery systems often suffer from premature drug leakage during transportation and/or inefficient drug release within cancer cells. We present here a polymeric prodrug nanoassembly that addresses these problems simultaneously. This nanoassembly comprises a polymeric prodrug with novel trivalent phenylboronate moieties for drug conjugation via ether linkages, as well as β-lapachone (Lapa). While the ether linkage enables nearly no drug release under physiological conditions, the Lapa molecules can induce the reactive oxygen species (ROS) burst specifically in cancer cells via NAD(P)H: quinone oxidoreductase-1 catalysis, which triggers the cleavage of the ether bonds and thus cascade amplification drug release in cancer cells...

β-lapachone has been found to be a highly potent anti-cancer agent in phase 1 clinical trials, but has dose limiting toxicity in red blood cells [Gerber et. al Br J Cancer. 2018 Oct;119(8):928-936]. Identifying a safe and quantitative method of monitoring treatment efficacy will be highly beneficial to establishing an adaptive dosing platform. Adaptative dosing can allow personalized treatments that significantly reduce off target effects while maintaining an effective therapeutic regimen. In this study we present the use of a safe and noninvasive tracer strategy utilizing both [2 H7 ]glucose and [U-13 C]glucose tracers to assess the metabolic effects caused by β-lapachone treatment in vitro...

Cancer, one of the major health problems all over the world, requires more competent drugs for clinical use. One recent possible chemotherapeutic drug under research is β-lapachone. β- lapachone (1,2-naphthoquinone) has promising activity against those tumors showing raised levels of Nicotinamide di-phosphate Quinone Oxidoreductases-1 (NQO1). NQO1 is found to be up-regulated in pancreatic tumor cells, and thus β-lapachone could generate cytotoxicity in various cancers like pancreatic tumors. β-lapachone harborage independent growth and clonogenic cell survival in agar...